The blood-labyrinth barrier (BLB) in the stria vascularis of the cochlea maintains endocochlear potential, ion transport, and fluid balance in the inner ear. Disruption of the BLB has long been considered a major etiologic factor in a variety of hearing disorders, including autoimmune inner ear disease, Meniere's disease, meningitis-associated labyrinthitis, and several genetically-linked diseases. Despite the importance of the BLB, however, the mechanisms that control BLB permeability remain largely unknown. A recent study from our lab unexpectedly found a large number of perivascular resident macrophage (PVMs) in the BLB, in addition to endothelial cells (ECs), basement membrane, and surrounding pericytes. The PVMs are in close contact with vessels through cytoplastic processes-end-feet-which contain a large number of vesicles and transporters. We hypothesize the PVMs and ECs are physiologically coupled for control of water and ion movement in the stria vascularis. In this project, we ask if PVMs contribute to the integrity of th BLB. If so, do PVMs control BLB integrity by affecting expression of tight and adherens junction proteins? Is the control mediated by pigment epithelial-derived factor? To test the hypothesis, we established a new primary EC and PVM cell co-culture model which we will use in association with a transgenic mouse model. The transgenic mice encode a diphtheria toxin receptor providing a system for transient depletion of PVMs. In addressing PVM control of BLB integrity, the proposed work will significantly enhance our understanding of the BLB at the cellular and molecular level and may ultimately lead to innovative treatments for BLB dysfunction-related hearing loss.